Therapeutic fcrn-based bispecific monoclonal antibodies

Abstract

The technology described herein is directed to immunotherapy agents for autoimmune disease, cancer, or allergy. In some embodiments, the immunotherapy agent comprises a bispecific antibody construct that specifically binds FcRn and a Type I or Type II Fcγ T receptor. In some embodiments the bispecific antibody construct is a DvD-Ig construct. Also described herein are methods for treating autoimmune disease, cancer, or allergy, comprising administering an effective amount of a bispecific antibody construct to patient in need thereof.

1 . A composition that selectively inhibits interaction between a type I Fc receptor or a type II Fc receptor, FcRn and an immunocomplexed antibody, the composition comprising a first binding domain that specifically binds a human type I Fc receptor or a human type II Fc receptor and a second binding domain that specifically binds a human FcRn. 
     
     
         2 .- 4 . (canceled) 
     
     
         5 . The composition of  claim 1 , wherein the first and second binding domains are comprised by a bispecific antibody construct. 
     
     
         6 . The composition of  claim 5 , wherein the bispecific antibody construct comprises a first binding domain comprising the CDRs of a V H /V L  domain pair that specifically binds a human type I Fc receptor or a human type II Fc receptor and a second binding domain comprising the CDRs of a V H /V L  domain pair that specifically binds a human FcRn. 
     
     
         7 . The composition of  claim 5 , wherein the bispecific antibody construct is selected from the group consisting of a tandem scFv (taFv or scFv 2 ), diabody, dAb 2 A/HH 2 , knob-into-holes bispecific derivative, SEED-IgG, heteroFc-scFv, Fab-scFv, scFv-Jun/Fos, Fab′-Jun/Fos, tribody, DNL-F(ab) 3 , scFv 3 -CH1/CL, Fab-scFv 2 , IgG-scFab, IgG-scFv, scFv-IgG, scFv 2 -Fc, F(ab′) 2 -scFv 2 , scDB-Fc, scDb-CH 3 , Db-Fc, scFv 2 -H/L, DVD-Ig, tandAb, scFv-dhlx-scFv, dAb2-IgG, dAb-IgG, or dAb-Fc-dAb construct. 
     
     
         8 .- 10 . (canceled) 
     
     
         11 . The composition of  claim 6 , wherein the bispecific antibody construct comprises a DvD-Ig construct. 
     
     
         12 . The composition of  claim 6 , wherein the V H  of the first V H /V L  domain pair is joined to the V H  of the second V H /V L  domain pair by a linker, and the V L  of the first V H /V L  domain pair is joined to the V L  of the second V H /V L  domain pair by a linker. 
     
     
         13 . (canceled) 
     
     
         14 . The composition of  claim 12 , wherein the linker is selected from the group consisting of GGSGGGGSG (SEQ ID NO: 202), GGSGGGGSGGGGS (SEQ ID NO: 204), TVAAP (SEQ ID NO: 203), and TVAAPSVFIFPP (SEQ ID NO: 205). 
     
     
         15 . The composition of  claim 12 , wherein the linker positions the first V H /V L  domain pair a distance of 10-100 Å away from the second V H /V L  domain pair, such that the composition preferentially binds FcRn and FcγR that are complexed with immunocomplexed immunoglobulin. 
     
     
         16 . The composition of  claim 12 , wherein the linker positions the first V H /V L  domain pair a distance of about 41 Å away from the second V H /V L  domain pair. 
     
     
         17 . The composition of  claim 6 , wherein the first V H /V L  domain pair is on the amino terminus of the bispecific antibody construct or the second V H /V L  domain pair on the amino terminus of the bispecific antibody construct. 
     
     
         18 .- 24 . (canceled) 
     
     
         25 . The composition of  claim 6 , wherein
 a. the first V H /V L  domain pair specifically binds a type I Fc receptor selected from the group consisting of CD32, CD32a, CD32b, CD32c, CD32a H , CD32a R , CD16, CD16a, CD16a V158 , CD16a F158 , and CD16b; or   b. the first V H /V L  domain pair specifically binds a type II Fc receptor comprising CD23 or DC-SIGN.   
     
     
         26 . (canceled) 
     
     
         27 . The composition of  claim 25 , wherein
 a. the V H /V L  domain pair that specifically binds CD32a binds an epitope or portion of a CD32a epitope selected from the group consisting of VKVTFFQNGKSQKFSRL (SEQ ID NO: 233), VKVTFFQNGKSQKFSHL (SEQ ID NO: 234), and NIGY (SEQ ID NO: 235);   b. the V H /V L  domain pair that specifically binds CD32b binds an epitope or portion of a CD32b epitope comprising FFQNGKSKKFSRSDPNFSI (SEQ ID NO: 236); or   c. the V H /V L  domain pair that specifically binds CD16a or CD16b binds an epitope or portion of a CD16a or CD16b epitope selected from the group consisting of HKVTYLQNGKDRKYFHH (SEQ ID NO: 237), LVGS (SEQ ID NO: 238), and LFGS (SEQ ID NO: 239).   
     
     
         28 .- 29 . (canceled) 
     
     
         30 . The composition of  claim 6 , wherein the V H /V L  domain pair that specifically binds FcRn binds an epitope or portion of an FcRn epitope selected from the group consisting of GPYT (SEQ ID NO: 230), ALNGEE (SEQ ID NO: 231), and DWPEALAI (SEQ ID NO: 232). 
     
     
         31 . The composition of  claim 25 , wherein:
 a. the V H /V L  domain pair that specifically contacts CD32a comprises a V H  CDR1 (SEQ ID NO: 1-SEQ ID NO: 9), a V H  CDR2 (SEQ ID NO: 23-SEQ ID NO: 31), a V H  CDR3 (SEQ ID NO: 45-SEQ ID NO: 53), V L  CDR1 (SEQ ID NO: 67-SEQ ID NO: 76), a V L  CDR2 (SEQ ID NO: 89-SEQ ID NO: 98), and a V L  CDR3 (SEQ ID NO: 113-SEQ ID NO: 122);   b. the V H /V L  domain pair that specifically contacts CD32b comprises a V H  CDR1 (SEQ ID NO: 9-SEQ ID NO: 22), a V H  CDR2 (SEQ ID NO: 31-SEQ ID NO: 44), a V H  CDR3 (SEQ ID NO: 53-SEQ ID NO: 66), V L  CDR1 (SEQ ID NO: 76-SEQ ID NO: 88), a V L  CDR2 (SEQ ID NO: 98-SEQ ID NO: 112), and a V L  CDR3 (SEQ ID NO: 122-SEQ ID NO: 134);   c. the V H /V L  domain pair that specifically contacts CD16a or CD16b comprises a V H  CDR1 (SEQ ID NO: 135-SEQ ID NO: 137), a V H  CDR2 (SEQ ID NO: 142-SEQ ID NO: 144), a V H  CDR3 (SEQ ID NO: 149-SEQ ID NO: 151), V L  CDR1 (SEQ ID NO: 156), a V L  CDR2 (SEQ ID NO: 161), and a V L  CDR3 (SEQ ID NO: 166);   d. wherein the V H /V L  domain pair that specifically contacts CD23 comprises a V H  CDR1 (SEQ ID NO: 138-SEQ ID NO: 139), a V H  CDR2 (SEQ ID NO: 145-SEQ ID NO: 146), a V H  CDR3 (SEQ ID NO: 152-SEQ ID NO: 153), V L  CDR1 (SEQ ID NO: 157-SEQ ID NO: 158), a V L  CDR2 (SEQ ID NO: 162-SEQ ID NO: 163), and a V L  CDR3 (SEQ ID NO: 167-SEQ ID NO: 168): or   e. the V H /V L  domain pair that specifically contacts DC-SIGN comprises a V H  CDR1 (SEQ ID NO: 140-SEQ ID NO: 141), a V H  CDR2 (SEQ ID NO: 147-SEQ ID NO: 148), a V H  CDR3 (SEQ ID NO: 154-SEQ ID NO: 155), V L  CDR1 (SEQ ID NO: 159-SEQ ID NO: 160), a V L  CDR2 (SEQ ID NO: 164-SEQ ID NO: 165), and a V L  CDR3 (SEQ ID NO: 169-SEQ ID NO: 170).   
     
     
         32 .- 35 . (canceled) 
     
     
         36 . The composition of  claim 6 , wherein the V H /V L  domain pair that specifically contacts FcRn comprises a V H  CDR1 (SEQ ID NO: 171-SEQ ID NO: 172), a V H  CDR2 (SEQ ID NO: 173-SEQ ID NO: 174), a V H  CDR3 (SEQ ID NO: 175-SEQ ID NO: 191), V L  CDR1 (SEQ ID NO: 192-SEQ ID NO: 193), a V L  CDR2 (SEQ ID NO: 194-SEQ ID NO: 196), and a V L  CDR3 (SEQ ID NO: 197-SEQ ID NO: 201). 
     
     
         37 .- 40 . (canceled) 
     
     
         41 . A method for modulating the interaction between a type I Fc receptor or a type II Fc receptor, FcRn and an immunocomplexed antibody, the method comprising contacting a cell with a composition of  claim 1 . 
     
     
         42 . The method of  claim 41 , wherein the composition does not modulate the binding of FcRn to monomeric antibodies. 
     
     
         43 . The method of  claim 41 , wherein modulating the binding of the type I Fc receptor or the type II Fc receptor and FcRn to immunocomplexed IgG occurs at a pH less than 7. 
     
     
         44 .- 56 . (canceled) 
     
     
         57 . A method of treating an autoimmune disease, comprising administering a therapeutically effective amount of a composition comprising a first binding domain that specifically binds a human type I Fc receptor or a human type II Fc receptor and a second binding domain that specifically binds a human FcRn to a subject in need thereof, wherein interaction between type I Fc receptor or type II Fc receptor and FcRn with an immunocomplexed antibody is reduced or inhibited. 
     
     
         58 .- 65 . (canceled) 
     
     
         66 . A method of treating cancer comprising administering a therapeutically effective amount of a composition comprising a first binding domain that specifically binds a human type I Fc receptor or a human type II Fc receptor and a second binding domain that specifically binds a human FcRn, wherein the composition is specific for CD32b and FcRn. 
     
     
         67 .- 75 . (canceled)